Down's syndrome is a genetic disorder (trisomy 21) associated with mental retardation that serves as a model for the study of Alzheimer's disease. Although post-mortem neuropathological studies reveal senile plaques and neurofibrillary tangles in almost all DS adults over the age of 40 years. This discrepancy between the neuropathological and clinical manifestations of AD in DS adults may be due to the lack of established sensitive neuropsychological measures in detecting early stages of dementia in DS. However, in our cross-sectional pilot study, the savings score from the California Verbal Learning test was used to define a group of DS believed to have early dementia. The rate of early dementia in these DS adults appeared to correspond with the age distribution of the AD neuropathology in this population. These results require confirmation with a longitudinal design on a large sample size of DS and Controls (matched by age and intelligence quotients with an age range of 20 to 60 + years) and is the focus of the proposed study. The proposed study will follow subjects over a five year period utilizing neuropsychological measures that have been successful in detecting early dementia in AD patients, but were not previously used in studies of dementia in DS. The study will determine the sensitivity of these measures, obtained upon initial assessment, in identifying DS adults showing a subsequent decline in cognitive function over time. The demented DS subjects will then be contrasted to non-demented DS and controls on a) prevalence of various putative AD risk factors, and b) blood levels of various proteins associated with AD; amyloid protein precursor (APP) and the beta-A4 domain of APP in plasma, and alpha-1-antichymotrypsin in the serum. Zinc and copper plasma levels will also be obtained since they may also be important in abnormal metabolism of APP, may be altered in DS and AD patients, and are cofactors for superoxide dismutase of which its gene is on chromosome 21. Based, on the results of our preliminary study on DS, we predict the presence of early dementia in DS adults with an age- distribution that corresponds with that of AD neuropathology. Furthermore, demented DS may differ from non-demented DS and Controls of prevalence of AD risk factors and on serological biochemical measures consistent with data on AD patients vs. controls.